The bulk of current Alzheimer's disease (AD) research is focused on possible interventions along the amyloid pathways however, this focused approach, may not ameliorate outcomes due to abnormal tau phosphorylation. In addition, AD is a complex and heterogeneous disease, with a diversity of risk factors and a multitude of symptoms. In the postgenomic era, identification of novel molecular targets for AD may offer the theoretical promise of great specificity coupled with reduced systemic toxicity, but this highly focused targeting approach faces the potential peril of being unable to deal successfully with a complex disease, such as AD. In contrast, targeting Hsp90, a cellular machinery that allows accumulation and progression of deregulated events, could provide a more comprehensive approach towards AD treatment. The ability of Hsp90 inhibitors to simultaneously affect multiple transforming molecules and pathways is a unique and therapeutically attractive feature of targeting this chaperone, suggesting that these inhibitors might provide a broader, more effective anti- neurodegenerative therapy than molecules targeting single signaling molecules that are the focus of most current drug discovery efforts. Moreover, the apparent increased requirement for Hsp90 activity in at least cancer and neurodegenerative diseases, suggests the real possibility of an exploitable therapeutic index for this approach. Our laboratory has pioneered the discovery and development of synthetic Hsp90 inhibitors, the purine-scaffold inhibitors (PU-class), and identified derivatives with favorable BBB-permeability profile. Administration of these molecules to AD transgenic mice resulted in induction of Hsp70, a chaperone able to partition tau into a productive folding pathway and to protect against Abeta and tau aggregate toxicity, and in modulation of aberrant neuronal proteins and a reduction in toxic tau aggregates, without toxicity to the mice. Based on these data, we propose here that the PU-class of Hsp90 inhibitors represents a multifaceted potential novel treatment to extend the survival of afflicted neurons, and focus the studies described in the U01 application on steps necessary for bringing these small molecule Hsp90 inhibitors to clinic as potential novel AD therapeutics. PUBLIC HEALTH RELEVANCE: Hsp90 inhibition offers a dual therapeutic approach in AD. First, it ameliorates protein misfolding by reduction of aberrant neuronal protein activity that leads to protein hyperphosphorylation and subsequent aggregation. Second, its benefit comes from induction of Hsp70, a chaperone able of redirecting neuronal aggregate formation, and of protective potential against both Abeta and tau aggregate toxicity.